Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) stimulates VLDL assembly through activation of cell death-inducing DFFA-like effector B (CideB).

Abnormalities in very low density lipoprotein (VLDL) assembly and secretion impact intrahepatic lipid homeostasis, plasma lipoprotein profile, and energy metabolism of distal peripheral tissues. We have evaluated the role of the transcriptional coactivator, the peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha), in VLDL assembly and secretion. PGC-1alpha overexpression in HepG2 cells led to diminished rates of triglyceride (TG) synthesis but strongly stimulated VLDL-TG secretion, markedly increasing the efficiency of secretion of newly synthesized TG. PGC-1alpha overexpression increased the rate of secretion of apoB100 and promoted secretion of larger, less dense VLDL particles. PGC-1alpha overexpression in intact mouse liver also stimulated rates of VLDL TG secretion and attenuated hepatic TG accumulation resulting from high fat diet feeding. To determine the molecular mechanisms mediating the effect of PGC-1alpha on VLDL assembly, we evaluated the expression of several candidate mediators known to be involved in VLDL assembly or hepatic lipid homeostasis. Cell death-inducing DFFA-like effector B (CideB) expression was greatly induced by PGC-1alpha, and siRNA against CideB reversed the effects of PGC-1alpha on the secretion of TG and VLDL-sized particles by HepG2 cells, indicating that CideB is a critical mediator of stimulatory effects of PGC-1alpha on VLDL secretion. Collectively, these data suggest that PGC-1alpha plays an important role in partitioning cytoplasmic TG toward the VLDL secretory compartments and promoting VLDL secretion via transcriptional induction of CideB.

ApoB100 is required for increased VLDL-triglyceride secretion by microsomal triglyceride transfer protein in ob/ob mice.

Microsomal triglyceride transfer protein (Mttp) is a key player in the assembly and secretion of hepatic very low density lipoproteins (VLDL). Here we determined the effects of Mttp overexpression on hepatic triglyceride (TG) and VLDL secretion in leptin-deficient (ob/ob) mice, specifically in relation to apolipoproteinB (apoB) isoforms. We crossed Apobec1(-/-) mice with congenic ob/ob mice to generate apoB100-only ob/ob mice (A-ob/ob). The obesity phenotype in both genotypes was similar, but A-ob/ob mice had greater hepatic TG content. Administration of recombinant adenovirus expressing murine Mttp cDNA (Ad-mMTP) increased hepatic Mttp content and activity and increased hepatic VLDL-TG secretion in A-ob/ob mice. However, despite equivalent overexpression of Mttp, there was no change in VLDL-TG secretion in ob/ob mice in a wild-type Apobec1 background. Metabolic labeling studies in primary hepatocytes from A-ob/ob mice demonstrated that Ad-mMTP increased triglyceride secretion without changing the synthesis and secretion of apoB100, suggesting greater incorporation of TG into existing VLDL particles rather than increased particle number. Ad-mMTP administration failed to increase hepatic VLDL secretion in lean Apobec1(-/-) mice or controls. By contrast, VLDL secretion increased and hepatic TG content decreased following Ad-mMTP administration to human APOB transgenic mice crossed into the Apobec1(-/-) line. These findings demonstrate that Ad-mMTP increases murine hepatic VLDL-TG secretion only in the apoB100 background, and even then only in situations with either increased hepatic TG accumulation or increased apoB100 expression.